Figure 7.

Schematic diagram depicting the proposed mechanisms underlying CCI-induced central sensitization and the development of mechanical allodynia. Peripheral nerve injury induces abnormal nociceptive signaling resulting in the subsequent release of mediators from primary afferents. D-serine can be produced by serine racemase activation in spinal astrocytes. D-serine released from astrocytes binds to the NMDA receptor glycine site and activates NMDA receptors with glutamate leading to increased Ca²⁺ influx into postsynaptic neurons. Ca²⁺/calmodulin-dependent activation of calcineurin then catalyzes the dephosphorylation of nNOS at the Ser847 site resulting in an increase in NO production. These NO signaling cascades are likely to stimulate PKC, which in turn induces phosphorylation of the PKC-dependent NMDA receptor GluN1 subunit at the Ser896 site, resulting in the development of central sensitization and ultimately leading to the development of mechanical allodynia associated with neuropathic pain. DAAO: D-amino acid oxidase; LSOS: L-serine O-sulfate potassium salt; NO: nitric oxide; PKC: protein kinase C; NMDAR: N-Methyl-D-aspartate receptor.